O-094 Pathological/theoretical viewpoint

Abstract

Abstract Endometriosis is a benign gynaecological disease. As the lifetime risk of developing an adenocarcinoma of the endometrium is about 2% in the general female population, there seems to be no reason to believe that the same type of mucosa should not undergo malignant derailments at a similar rate when displaced at ectopic sites. The endometrioid ovarian carcinomas and the clear cell ovarian carcinomas are the most frequent histotypes associated with endometriosis. However, determining whether the mere presence of endometrium at ectopic sites should be considered per se a premalignant condition seems crucial and constitutes the conceptual base of any strategy aimed at preventing and treating endometriosis-associated ovarian cancer. Lesions are defined “precancerous” based on definite epidemiologic, morphologic, molecular, and biologic criteria that imply the acquisition of genetic, karyotypic, structural, or functional changes in a cluster of cells that differentiate them from the surrounding normal tissue. In other words, premalignant lesions should reflect an intermediate stage along the pathway leading to cancer. The transformation of a normal cell into a cancer cell is due to the progressive acquisition of driver mutations. With the improvement of sequencing technology, several studies focusing on genomic features or molecular targets have been performed in endometriosis. In particular, studies have evaluated somatic cancer-associated mutations in endometriotic lesions without concurrent cancer to assess whether endometriosis might be considered as a precursor of cancer. It has been reported recently that several ovarian and deep endometriosis lesions harbour cancer-associated mutations. Cancer-driver mutations involve genes coding for AT-rich interactive domain-containing protein 1A (ARID1A), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA), Kirsten rat sarcoma (KRAS), or protein phosphatase 2 scaffold subunit Aα (PPP2R1A). These mutations are quite frequent also in deep endometriosis and this result is surprising considering that deep infiltrating endometriotic lesions very rarely undergo malignant transformation. This poses some doubts on the real oncogenic potential of these mutations. On the other hand, a specific role seems to be played by the ovarian microenvironment in increasing the risk of malignant derailment. The chronic inflammatory environment of women with endometriosis may theoretically facilitate the transformation of abnormal endometrial cell into a malignant cell. The micro-environmental factors such as oxidative stress, immune cell dysfunction, steroid hormones, and stem cells required for malignant transformation have been found in endometriosis. Driver gene mutations have been identified at the genetic level also in the normal endometrium, which is the origin of endometriosis. The next issue is to clarify a trigger of carcinogenesis based on genomic lineage from normal endometrium to ovarian cancers via endometriosis. To address these issues, multiomics analysis combining genomics, transcriptomics, and proteomics will be necessary.